With the exception of transferrin, desialyated human serum glycoproteins are promptly removed from the circulation by the parenchymal cells of the liver. The primary binding site for the asialoproteins has been identified as the liver plasma membrane and the parameters of glycoprotein binding in vitro closely parallel those required for clearance in vivo. An in vitro assay system has been developed that is capable of providing a quantitative measure of binding and that provides an experimental model for a detailed examination of the structural determinants of glycoprotein binding as well as the binding phenomenon itself. Although termination of the carbohydrate chains by intact, nonreducing galactose is a major determinant of binding and clearance, it is neither unique nor sufficient to explain the broad spectrum of glycoprotein binding behavior observed. The role of the protein backbone, the participation of critical amino acids present in oligosaccharide-protein linkage regions and the structural specificity of the individual oligosaccharide chains, all require quantitative evaluation. The proposed investigation will provide such information on the additional structural determinants of binding. Exposure of membranes to neuraminidase results in loss of the binding capacity and partial recovery has been demonstrated upon enzymatic restoration of the salic acid residues. Consequently, the participation of the membrane associated carbohydrates will be examined. A major fraction of the plasma proteins are glycoproteins and it is known that their concentration varies specifically in various normal and physiological and disease states, both malignant and nonmalignant. These studies will lead to a better understanding of the normal pathways of glycoprotein catabolism and should add to the understanding of the alternations that occur in abnormal states.